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Novel Human Corticosteroid-Binding Globulin Variant with Low Cortisol-Binding Affinity¹

Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique (A.E.-B., P.C., M.P.) and Département d’Endocrinologie (C.B.), Hôpital de l’Antiquaille, 69321 Lyon Cedex 05; INSERM U 329, Hôpital Debrousse, 69005 Lyon, France; and Departments of Obstetrics and Gynecology and Parmacology and Toxicology, University of Western Ontario and London Regional Cancer Centre (K.S., G.V.A., G.L.H.), N6A 4L6 London, Ontario, Canada

Address correspondence and requests for reprints to: Michel Pugeat, Laboratoire de la Clinique Endocrinologique, Hôpital de l’Antiquaille, 1 rue de l’Antiquaille, 69321 Lyon Cedex, France. E-mail: laboendo{at}cismsun.univ-lyon1.fr

Corticosteroid-binding globulin (CBG) is the plasma transport protein that regulates the access of glucocorticoid hormones to target cells. Genetic deficiencies of CBG are rare, and only a single human CBG variant (Trancortin Leuven) has been related so far to decreased cortisol-binding affinity. We report here on a 43-yr-old woman, referred for chronic asthenia and hypotension, with repeatedly low morning serum cortisol levels (22–61 nmol/L; normal range, 204–546 nmol/L), normal plasma ACTH levels (38–49 pg/mL; normal, <50 pg/mL), and normal urinary cortisol (10–76 nmol/24 h; normal range, 10–105 nmol/24 h). An increased percent-free (dialysable fraction) serum cortisol (8.7–9.7%, normal range, 2.9–3.9%) suggested abnormal CBG binding activity. Indeed, she had a low serum CBG concentration (24 mg/L vs. 44 ± 6 mg/L in normal women), and the affinity of her CBG for cortisol was decreased (association constant, Ka = 0.12 L/nmol vs. 0.82 ± 0.29 L/nmol). In her immediate family members, the serum CBG concentration and cortisol-binding activity were normal in her husband, but the four living children had slightly lower serum CBG concentrations than the reference ranges for their pre- and postpubertal status. Measurements of cortisol distribution in undiluted serum indicated that an increase in the percentage of nonprotein-bound cortisol offsets the low cortisol levels to give approximately normal concentrations of free cortisol in serum. Direct sequencing of PCR-amplified exons encoding CBG revealed that the proband was homozygous for a polymorphism (GACAAC) in the codon for residue 367, which results in a Asp³⁶⁷Asn substitution. Her children were heterozygous for this polymorphism. When this nucleotide change was introduced into a normal human CBG complementary DNA, for expression in Chinese hamster ovary cells, Scatchard analysis demonstrated that the Asn³⁶⁷ substitution reduced the affinity of human CBG for cortisol by approximately 4-fold (Ka = 0.15 L/nmol), as compared to normal recombinant CBG (Ka = 0.66 L/nmol). These results suggest that Asp³⁶⁷ is an important determinant of CBG steroid-binding activity and that normal negative regulation of the hypothalamic-pituitary-adrenal axis is maintained by relatively normal serum-free cortisol concentrations, despite a marked reduction in the steroid-binding affinity of this novel human CBG variant, which we have designated as CBG-Lyon.

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